The filling operation for bulk drug substances is a critical final step that requires sterile processing to assure product quality. It is imperative that the manufacturer be able to determine that the final assembly is integral prior to quality assurance release. Indeed, as the market for biopharmaceuticals continues to grow, manufacturers must be certain to follow the strict regulatory guidelines for the production of these drugs. Because most biopharmaceuticals are administered by injection, their sterility is crucial to the safety of the patient receiving the drug therapy. Filtration is a critical quality-assurance strategy for injectable drugs. In guidelines published in 2004, the US Food and Drug Administration suggested the use of redundant sterilizing filters. This is generally defined as a type of serial filtration in which a second sterilizing-grade filter is used as a backup in the event of an integrity failure of the primary sterilizing filter. The second sterilizing-grade filter is incorporated in line, usually upstream but possibly downstream, to provide additional assurance of sterilizing filtration. This can be particularly important for batches that cannot be reworked in the event of a sterilizing filter integrity failure, resulting in complete loss of the batch often at consideration expense.
While redundant sterile filtration reduces the risk of losing a batch due to an integrity failure, it introduces considerable complication to the process. Typically the filters are flushed, integrity tested and dried before use. When configured in a redundant sterile filtration mode, any point downstream of the first filter must remain sterile. This requires the use of additional air and drain filters to allow the pre-use preparation. It also requires a significant amount of operator interaction to open and close numerous valves in the correct sequence to carry out the various flushing, testing and drying operations. This complication and chance for operator error introduces the opportunity of breaching sterility or creating some other failure type. Most significant, however, is the increase in product loss due to the increased working volume. Product cost is often in the hundreds of dollars per milliliter, so even small losses can be costly.
Where redundant filtration is employed, typically it involves using two sterilizing grade 0.2 μm hydrophilic capsule filters in series. However, this presents several issues, since hydrophilic filters will not allow air passage once wet. Venting air from the capsules requires either a separate sterile vent filter or more commonly a closed, sterile waste reservoir to vent into. Pre-use integrity testing of the capsules requires an intermediate drain filter between them to allow downstream flow. Drying the cartridges before introducing product requires exceeding the bubble point pressure of the membrane with compressed air for approximately 20 minutes. When two capsules are attached in series, it is typically difficult to execute this drying step due to the additive pressure drop across both devises and the overall working pressure rating of the housings. For this reason, the capsules are typically dried separately through the intermediate drain filter and an additional air inlet filter placed before the second sterile filter.
Given the extremely low failure rate of the existing single stage filtration system, the added complexity of redundant filtration is difficult to justify financially. However, if that complexity could be reduced or eliminated, the benefit of redundant sterile filtration could be realized.
It therefore would be desirable to provide a device and methodology that utilizes redundant filtration with ease of use and product yield comparable to single stage solutions.